A number of review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists; Eicosanoids: From Biotechnology to therapeutic Applications, Folco, Samuelson, Maclouf and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154; “Molecular aspects of the structures and functions of the prostaglandin E receptors”, Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87; “Function of prostanoid receptors: studies on knockout mice”, Prostaglandins & other Lipid Mediators, 2002, 68-69, 557-573 and “Prostanoid receptor antagonists: development strategies and therapeutic applications”, British Journal of Pharmacology (2009), 158, 104-145. Prostaglandin E2 (PGE2) is a member of the prostanoid family with a variety of physiological effects, including mucosal protection, induction of gastric acid secretion in stomach, generation of fever, hyperalgesia, inflammation and immunity. These actions of PGE2 are mediated by four G-protein-coupled PGE2 receptors, EP1, EP2, EP3 and EP4.
The EP4 receptor is a 7-transmembrane receptor whose activation is normally associated with elevation of intracellular cyclic adenosine monophosphate (cAMP) levels. PGE2-activated EP4 receptor signalling may be involved in various pathologic states, such as pain (in particular inflammatory, neuropathic and visceral), inflammation, neuroprotection, cancer, dermatitis, bone disease, immune system dysfunction promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion.
In The Journal of Immunology (2008) 181, 5082-5088, studies suggest that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in osteoarthritic chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for osteoarthritis disease modification.
In European Journal of Pharmacology (2008) 580, 116-121, studies suggest that a pharmacological blockade of the prostanoid EP4 receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.
A number of publications have demonstrated that PGE2 acting through the EP4 receptor subtype, and EP4 agonists alone, can regulate inflammatory cytokines after an inflammatory stimulus. Takayama et al in the Journal of Biological Chemistry (2002) 277, 46, 44147-54, showed that PGE2 modulates inflammation during inflammatory diseases by suppressing macrophage derived chemokine production via the EP4 receptor. In Bioorganic & Medicinal Chemistry (2002) 10, 7, 2103-2110, Maruyama et al demonstrate the selective EP4 receptor agonist ONO-AE1-437 suppresses LPS induced TNF-a in human whole blood whilst increasing the levels of IL-10. An article from Anesthesiology, (2002) 97, 170-176, suggests that a selective EP4 receptor agonist ONO-AE1-329 effectively inhibited mechanical and thermal hyperalgesia and inflammatory reactions in acute and chronic monoarthritis.
Two independent articles from Sakuma et al in Journal of Bone and Mineral Research (2000) 15, 2, 218-227 and Miyaura et al in Journal of Biological Chemistry (2000) 275, 26, 19819-23, report impaired osteoclast formation in cells cultured from EP4 receptor knock-out mice. Yoshida et al in Proceedings of the National Academy of Sciences of the United States of America (2002) 99, 7, 4580-4585, by use of mice lacking each of the PGE2 receptor EP subtypes, identified EP4 as the receptor that mediates bone formation in response to PGE2 administration. They also demonstrated a selective EP4 receptor agonist (ONO-4819) consistently induces bone formation in wild type mice. Additionally, Terai et al in Bone 2005, 37(4), 555-562 have shown the presence of a selective EP4 receptor agonist (ONO-4819) enhanced the bone-inducing capacity of rhBMP-2, a therapeutic cytokine that can induce bone formation.
Further research by Larsen et al in Acta. Physiol. Scand. (2005) 185, 133-140, shows the effects of PGE2 on secretion in the second part of the human duodenum is mediated through the EP4 receptor. Nitta et al in Scandinavian Journal of Immunology (2002), 56, 1, 66-75 has shown that a selective EP4 receptor agonist ONO-AE 1-329 can protect against colitis in rats.
Dore et al in The European Journal of Neuroscience (2005) 22, 9, 2199-206, have shown that PGE2 can protect neurons against amyloid beta peptide toxicity by acting on EP2 and EP4 receptors. Furthermore Dore has demonstrated in Brain Research (2005) 1066, (1-2), 71-77 that an EP4 receptor agonist ONO-AE1-329 protects against neurotoxicity in an acute model of excitotoxicity in the brain.
Woodward et al in Journal of Lipid Mediators (1993), 6, (1-3), 545-53, found intraocular pressure could be lowered using selective prostanoid agonists. Two papers in Investigative Ophthalmology & Visual Science have shown the prostanoid EP4 receptor is expressed in human lens epithelial cells (Mukhopadhyay et al 1999, 40(1), 105-12), and suggest a physiological role for the prostanoid EP4 receptor in modulation of flow in the trabecular framework of the eye (Hoyng et al 1999, 40(11), 2622-6).
Compounds exhibiting EP4 receptor binding activity and their uses as agonists have been described in, for example WO2009150118, WO2008136519, WO2008092860, WO2008092861, WO2008092862, WO2006137472, JP2006321737, WO2006052630, WO2006052893, WO2006016689